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Chapter 11 : Cryoglobulins, Cryofibrinogenemia, and Pyroglobulins

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Abstract:

Cryoglobulins are immunoglobulins (Igs) that precipitate out of solution below core body temperatures, either as a single isotype (simple cryoglobulins) or as immune complexes in which both antibody and antigen are Igs (mixed cryoglobulins). Mixed cryoglobulins are cold-precipitable rheumatoid factors (RFs), with the serum often being positive when standard assays for IgM antiglobulin activity are used. Although many clinical laboratories offer cryoglobulin determinations, rarely is testing rigorously carried out, and there is considerable interlaboratory variability. A search for cryofibrinogenemia may be dictated by unexplained thrombohemorrhagic coagulopathy or cold-dependent purpura; it may also be dictated by the finding of characteristic pathology, occurring in various affected organs, as for example an occlusive thrombotic diathesis due to eosinophilic deposits within vessel lumina, extending into the intima, which may be associated with a granulomatous vasculitic component. Cryofibrinogenemia can be screened by cryoprecipitating or freeze-thawing plasma collected in citrate that contains an inhibitor of thrombin generation and is most convincing in the absence of coexisting cryoglobulinemia. Recognition of the laboratory phenomenon of pyroglobulinemia has importance as a potentially confounding factor for heat-based assays used to inactivate complement or to measure fibrinogen levels. Proper identification of a pyroglobulin as being a monoclonal component may in turn lead to the diagnosis of macroglobulinemia or plasma cell dyscrasia.

Citation: Gorevic P, Galanakis D. 2006. Cryoglobulins, Cryofibrinogenemia, and Pyroglobulins, p 101-111. In Detrick B, Hamilton R, Folds J (ed), Manual of Molecular and Clinical Laboratory Immunology, 7th Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815905.ch11

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Clinical Immunology
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Agarose Gel Electrophoresis
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Hepatitis C virus
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Figures

Image of FIGURE 1
FIGURE 1

Cryoglobulinemia was initially missed in a patient with cutaneous vasculitis documented by biopsy of a purpuric lesion on the right second digit (A, left panel). Because of deteriorating status, including renal failure, she was treated with high doses of steroids and then cytotoxic agents, with apparently poor response in terms of an expected drop in leukocyte count. One weekend, while still in the intensive care unit, the patient was noted to have developed nasal purpura in the distribution of a cold-air oxygen mask (A, right panel). The Coulter histograms obtained at 4, 25, and 37°C (B) display the leukocyte (top), erythrocyte (middle), and platelet (bottom) panels. The leukocyte panel shows small lymphocytes to the left (thin arrow) and larger polymorphonuclear leukocytes and monocytes to the right (thick arrow), with the ordinate displaying percent total cells; the platelet panels at 4 and 25°C are unusual in having a long tail (*) after the expected narrow peak. Pseudoleukocytosis and pseudothrombocytosis are revealed at 37°C, which shows (i) all the leukocytes to be polymorphonuclear, with few lymphocytes, as expected for a patient on high-dose corticosteroids; and (ii) a narrow platelet peak. Both findings are reflected in the manual counts (B, right). Recognition of this artifact led to identification of a type II cryoglobulin with RF activity, with restricted IgM and κ arcs by immunoelectrophoresis (C, arrowheads) and a high thermal amplitude of cryoprecipitation (D). OD, optical density.

Citation: Gorevic P, Galanakis D. 2006. Cryoglobulins, Cryofibrinogenemia, and Pyroglobulins, p 101-111. In Detrick B, Hamilton R, Folds J (ed), Manual of Molecular and Clinical Laboratory Immunology, 7th Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815905.ch11
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Image of FIGURE 2
FIGURE 2

Kinetics of cryoprecipitation, assessed by turbi-metric analysis, for a type II cryoglobulin, comparing serum and isolated cryoglobulin (A), different concentrations of isolated cryoglobulin (B), and different temperatures of cryoprecipitation (C). OD, optical density.

Citation: Gorevic P, Galanakis D. 2006. Cryoglobulins, Cryofibrinogenemia, and Pyroglobulins, p 101-111. In Detrick B, Hamilton R, Folds J (ed), Manual of Molecular and Clinical Laboratory Immunology, 7th Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815905.ch11
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Image of FIGURE 3
FIGURE 3

Isolated washed cryofibrinogen (arrows) visualized by agarose gel electrophoresis (left) and immunofixation (right). Gel electrophoresis reveals some residual albumin toward the anode, fibronectin in the β region, an origin artifact, and fibrinogen, compared to serum samples in the upper and lower lanes. In the immunofixation on the right, an origin artifact is seen in all lanes due to precipitation on the cold gel. However, the antifibrinogen lane shows increased precipitate, thereby characterizing this as fibrinogen. (Figure generously provided by D. Keren.)

Citation: Gorevic P, Galanakis D. 2006. Cryoglobulins, Cryofibrinogenemia, and Pyroglobulins, p 101-111. In Detrick B, Hamilton R, Folds J (ed), Manual of Molecular and Clinical Laboratory Immunology, 7th Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815905.ch11
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Image of FIGURE 4
FIGURE 4

Reversible cryogel formation at 4°C (tube inverted) and 37°C (liquid).

Citation: Gorevic P, Galanakis D. 2006. Cryoglobulins, Cryofibrinogenemia, and Pyroglobulins, p 101-111. In Detrick B, Hamilton R, Folds J (ed), Manual of Molecular and Clinical Laboratory Immunology, 7th Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815905.ch11
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References

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Tables

Generic image for table
TABLE 1

Classification of cryoglobulins

Citation: Gorevic P, Galanakis D. 2006. Cryoglobulins, Cryofibrinogenemia, and Pyroglobulins, p 101-111. In Detrick B, Hamilton R, Folds J (ed), Manual of Molecular and Clinical Laboratory Immunology, 7th Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815905.ch11
Generic image for table
TABLE 2

Disease, clinical, and laboratory associations

Citation: Gorevic P, Galanakis D. 2006. Cryoglobulins, Cryofibrinogenemia, and Pyroglobulins, p 101-111. In Detrick B, Hamilton R, Folds J (ed), Manual of Molecular and Clinical Laboratory Immunology, 7th Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815905.ch11
Generic image for table
TABLE 3

Laboratory abnormalities in cryoglobulinemia

Citation: Gorevic P, Galanakis D. 2006. Cryoglobulins, Cryofibrinogenemia, and Pyroglobulins, p 101-111. In Detrick B, Hamilton R, Folds J (ed), Manual of Molecular and Clinical Laboratory Immunology, 7th Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815905.ch11

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